Description: The mechanisms responsible for the cellular degeneration seen in neurodegenerative disorders like ALS, AD and other dementias is not well understood. Loss of certain proteins such as the astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2) has been found in ALS and AD. Loss of EAAT2 can lead to increased extracellular glutamate and excitotoxic neuronal degeneration. Recent studies document multiple abnormal EAAT2 mRNAs, including intron-retention and exon-skipping, in the affected tissues from neurodegenerative disease specimens. The aberrant mRNAs were highly abundant and were only found in neuropathologically affected brain regions. These truncated mRNA species suggest an underlying defect in mRNA processing in astroglia. Evolving data suggest that CNS insults can induce expression of cellular or RNA-specific mRNA processing proteins. This project will employ a systematic approach to study the biology and relevance of aberrant EAAT2 mRNA and protein in neurodegeneration. The project will identify and characterize aberrant EAAT2 mRNA species and proteins in several distinct neurodegenerative conditions (frontotemporal dementia, Huntington's disease, spinal muscular atrophy, hereditary ataxia) along with transgenic models of some of these disorders. In those disorders with identified abnormalities in astroglial mRNA processing, the PL will culture astrocytes from human and animals tissues to establish in vitro systems. Finally, the study will use these in vitro systems to investigate the mechanism of abnormal mRNA processing and will examine novel and established genes/proteins that may be responsible for the defect in mRNA processing. Preliminary work suggests that the loss of EAAT2 in ALS and AD is due to aberrant mRNA, and these aberrant mRNAs could result from RNA processing errors. Aberrant RNA processing could be an important process in the pathophysiology of neurodegenerative diseases and in excitotoxicity.